This is the first report of lengthy follow-up, detailed neurological testing, and advanced spinal cord imaging of a patient with apparent intramedullary injection during cervical ESI. We know of only 3 prior published cases [22
]. In addition to immediate damage, the advanced MRI techniques used, including a new highly sensitive coil and multiple sequences able to distinguish white-matter degeneration from demyelination, revealed previously unreported delayed radiological changes most consistent with Wallerian degeneration of the injected ascending dorsal column. However, measurement of central motor conduction time (CMCT) after transcranial magnetic stimulation was the only test that identified the correlate of her motor deficits. CMCT demonstrated that the injury extended beyond the radiologically visualized lesion to involve the corticospinal tract; thus, radiological imaging alone may be insufficient to document the extent of such injuries.
Injecting into the spinal cord is universally contraindicated. Needlestick alone can cause injury, but in this case there was almost certainly additional injury from injectate, based on development of a cavitary lesion plus involvement of more than one spinal cord tract. Injectate can injure by mechanical disruption of nearby cells, chemical toxicity, and high osmolarity that triggers later disruption from edema. The small size of the cavity does not necessarily predict the volume of injectate within the spinal cord because radiological/pathological correlations are unestablished. We considered which among the specific injections and injectates was causal. Intra-procedural fluoroscopy reportedly exonerated the contrast. The patient reportedly first complained of symptoms during local-anesthetic administration, but a 1.5″ needle could not easily cause this lesion even with skin depression. A needle would have to traverse 2.26″ to cause a 1.6″ deep injury, assuming a 45 degree caudal angle was used to penetrate between the angled spinous processes. Plus, local anesthetics acutely cause flaccid paresis, not the muscle spasms and increased tone documented. Thus the Depo-Medrol injection appears the most likely cause.
Intrathecal injections of various substances including water are often neurotoxic and have caused multiple cases of human paraparesis associated with both demyelination and axonal degeneration [17
]. Depo-Medrol is explicitly contraindicated for intrathecal administration and is intermediate in neurotoxicity among tested preparations [2
]. Pathological study demonstrates it can cause axonal and myelin degeneration plus disruption of the blood-nerve barrier when injected into peripheral nerves [31
]; there are no data concerning effects of injection into brain or spinal cord. Depo-Medrol contains two other constituents in addition to methylprednisolone acetate. Polyethylene glycol is a water-soluble polymer used as a dispersant; low concentrations are non-toxic to nerve [3
]. Benzyl alcohol (α-hydroxytoluene) is a bacteriostatic agent. When Depo-Medrol purified of its additives was intrathecally administered to dogs, this produced focal meningeal and intramedullary inflammation but no overt neuronal pathology [39
], suggesting that the additives are more neurotoxic than the methylprednisolone. The radiological findings in this case are consistent with Depo-Medrol toxicity.
The new 32-channel receive coil, designed to maximize sensitivity in the cervical spinal cord, doubled the signal-to-noise ratio compared to standard commercial cervical spine coils [11
]. To obtain the same signal-to-noise ratio using a commercial coil with half the sensitivity would require quadrupling acquisition time. The new coil enabled us to complete multiple high resolution sequences in a clinically feasible acquisition time (48 minutes). These revealed abnormal signal change most consistent with delayed Wallerian degeneration of ascending sensory tracts. Similar T2
* hyperintense signal was detected in the cervical cord of a patient with chronic spinal-cord injury using ultra-high field 7T MRI [12
]. Since T2
hyperintensity is not specific for pathological components, i.e. axon injury, myelin injury, or both [25
], DTI and MT measures were performed to better characterize the white matter pathology. Animal [4
] and human [8
] studies of Wallerian degeneration suggest that changes in axial diffusivity are relatively specific for axonal degeneration and changes in radial diffusivity are relatively specific for demyelination. The schematic in illustrates these changes in DTI parameters at the acute, subacute and chronic phase of Wallerian degeneration, based on previous studies [30
]. Acutely (hours to weeks), axonal fragmentation creates barriers to axial water mobility, reducing axial diffusivity. In the subacute through early-chronic phase (months to one year), activated microglia clear axonal debris, normalizing or even elevating axial diffusivity. In the late-chronic phase (years), astrocytic scarring can impede axial water mobility and decrease diffusivity. Radial diffusivity increases during the subacute to early chronic phase as myelin debris is cleared and it remains high during the late chronic phase. During all stages, the combined changes of axial diffusivity and radial diffusivity cause decreased FA, which is therefore less physiologically specific. Wallerian degeneration is very slow in the CNS, and can last up to 8 years [7
Schematic depicting how DTI metrics change with time after injury. Radial diffusivity (RD) and axial diffusivity (AD) provide more specificity to various stages of white matter pathology compared to fractional anisotropy (FA).
In this patient, DTI at 8 and 12 months post-injury showed increased radial diffusivity (i.e, myelin breakdown), unchanged axial diffusivity (likely pseudonormalization after axon degeneration), and decreased FA in the left dorsal cord from C5 to C2, rostral to the C5–6 cavitary lesion. These DTI metrics most likely identify subacute to early chronic Wallerian degeneration. MT imaging evaluates interaction between the relatively immobile macromolecular (i.e., myelin) protons and mobile free-water protons [19
]. MTR decreases in proportion to demyelination [15
]. MTR measurements have been difficult in the cervical cord because of low signal-to-noise ratio and spinal cord movement during respiration. The alternative we used, CSF-normalized MT imaging (MTCSF), mitigates these [41
]. However, it does not normalize for variations in spin density and T1
relaxation times. If spin density, T1
, and T2
are normal, then increased MTCSF reflects pure magnetization transfer effects that can be specifically attributed to demyelination. In this study, T2
- and T2
*-weighted signal intensity were abnormal in the left dorsal cord, so the MTCSF hyperintensity might therefore reflect magnetization transfer, T2
/spin density, or both [41
]. However, lower MTR at 51 weeks post-injury in the left dorsal cord confirmed magnetization transfer effects, suggesting demyelination. Thus, both DTI and MT imaging revealed demyelination in the left ascending dorsal cord, consistent with evolving Wallerian degeneration.
We also evaluated the utility of other non-radiological tests for this spinal cord injury. The normal results of electromyography and nerve conduction study served to exclude peripheral causes. Somatosensory evoked potentials, which assess the dorsal column/medial lemniscal pathway, were interpreted as normal. SSEP recordings are known to be relatively insensitive, and can remain normal in patients with significant sensory deficits or lesions, as here. However, abnormal SSEP results have high positive predictive value for somatosensory-tract lesions. Measurement of CMCT after transcranial magnetic stimulation was the most useful non-radiological test, providing the only objective correlate of the patient’s persistent left-predominant corticospinal-tract damage (). Previous studies reported excellent correlation between CMCT measurements and intramedullary MRI findings in patients with cervical spondylotic myelopathy [29
] but here, CMCT study was more sensitive than even the most advanced MRI for detecting subtle corticospinal-tract abnormality. The current study suggests that advanced MRI techniques plus additional physiological diagnostic tests should be considered to more fully identify the extent of injury after focal cervical spinal cord injuries.